Date of Graduation

8-2017

Document Type

Thesis

Degree Name

Master of Science in Kinesiology (MS)

Degree Level

Graduate

Department

Health, Human Performance and Recreation

Advisor

Nicholas P. Greene

Committee Member

Tyrone A. Washington

Second Committee Member

Walter G. Bottje

Keywords

Atrophy, Cachexia, Cancer, Muscle, Sequencing, Transcriptomics

Abstract

Introduction: Cancer is a major public health problem in the U.S. and the world. In 2013 there were an estimated 1,660,290 new cases of cancer in the U.S. Cancer-Cachexia (CC) is a common effect of many cancers, and is directly responsible for 20-40% of cancer-related deaths. The mechanisms that control the development of CC are not well understood. Most investigations of CC focus on the post-cachectic state and do not examine the progression of the condition. The purpose of this study was to utilize RNA sequencing to analyze transcriptomic alterations throughout the progression of CC. Methods: Lewis Lung Carcinoma cells (LLC) or Phosphate Buffered Saline (PBS, control) were injected into the hind-flank of wildtype C57BL6/J mice at 8 wks of age, and tumor allowed to develop for 1, 2, 3, or 4 wks before euthanasia. RNA was isolated from the gastrocnemius and RNA sequencing performed. Results: RNA sequencing showed widespread alterations in LLC when compared to PBS animals with largest differences seen in 4 wk LLC compared to other conditions. Commonly altered pathways included: Oxidative Phosphorylation, Mitochondrial Dysfunction, and Protein Ubiquitination. Discussion: We demonstrated that alterations in the muscle belly likely occur in phases beginning with early mitochondrial degenerations, which now appear to lead to large transcriptomic shifts concurrent to the onset of muscle atrophy. In agreement with previous work, we observed multiple aspects related to degeneration of mitochondria and oxidative metabolism. The early onset of these alterations shows a need for early interventions in order to effectively ameliorate the effects of CC.

Available for download on Sunday, September 15, 2019

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